The use of fenofibrate in the management of patients with diabetic retinopathy: an evidence-based review.

BACKGROUND: Diabetic retinopathy is a significant cause of vision impairment, especially affecting those of working age. There are two large, randomised controlled trials examining the effect of fenofibrate on diabetic retinopathy. OBJECTIVE: We summarise their findings, and report on the available safety data. DISCUSSION: The FIELD study reported that patients treated with fenofibrate had a statistically significant relative risk reduction in the need for laser treatment for maculopathy and proliferative retinopathy. The ACCORD-Eye study reported a statistically significant reduction in diabetic retinopathy progression in patients treated with fenofibrate and statin combination therapy compared to statin therapy alone. There is firm evidence that fenofibrate slows the progression of diabetic retinopathy and the need for more invasive treatment modalities in patients with type 2 diabetes, especially those with pre-existing retinopathy. In October 2013, Australia became the first country in the world to approve the use of this medication for this specific indication.

Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice.

Inflammatory processes have an important role in the development of hepatic steatosis and progression to nonalcoholic steatohepatitis (NASH). Interleukin-6 (IL-6) is known to be a proinflammatory cytokine, but also promotes liver regeneration and protects the liver against various forms of damage. The role of IL-6/Glycoprotein 130 (GP130) in NASH remains unclear. In this study, we determined whether blocking IL-6/GP130 signaling prevents progression of steatohepatitis in a mouse NASH model. Six-week-old male C57/BL6 mice were fed either chow control or a methionine choline-deficient (MCD) diet for 8 weeks. Half of the MCD diet-fed mice were treated with 15 mg/kg rat anti-mouse IL-6 receptor antibody (MR16-1), intraperitoneally twice weekly, the remainder and chow-fed mice were injected with 15 mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, apoptosis, markers of lipid peroxidation/oxidant stress and IL-6-related gene expressions were evaluated. MR16-1 treatment decreased signal transducer and activator of transcription 3 activities and expression of suppressor of cytokine signaling 3 in MCD diet-treated mouse livers. Although this treatment enhanced intrahepatic lipid accumulation accompanied by increased sterol regulatory element-binding protein 1 and decreased peroxisome proliferator-activated receptor-alpha expression, elevated plasma alanine aminotransferase levels were improved with decreased plasma free fatty acid levels, lipid peroxidation/oxidant stress and hepatic apoptosis. Blocking IL-6/GP130 signaling by MR16-1 enhanced MCD diet-induced hepatic steatosis, but ameliorated liver injury. These findings suggest that hepatic IL-6 signaling has a protective role against the progression of hepatic steatosis but may enhance liver inflammation.

Effects of PPARalpha on cardiac glucose metabolism: a transcriptional equivalent of the glucose-fatty acid cycle?

Cardiovascular disease is exceptionally prevalent in patients with diabetes mellitus and is the most common cause of death. With the emerging pandemic of obesity and resulting metabolic abnormalities, the occurrence of cardiovascular disease is almost nearly certain to increase at a remarkable rate in the near future. Currently, several ligands for the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors are prescribed as lipid-lowering and insulin-sensitizing drugs. The PPARs are ligand-activated transcription factors that influence the expression of the entire program of fatty acid utilization enzymes. It is believed that these compounds remedy glucose homeostasis and cardiovascular disease by lowering circulating lipid levels, improving the profile of secreted adipokines, as well as via their anti-inflammatory properties. Conversely, overexpression of the PPARalpha isoform in the muscle or heart of mice drives diminished glucose transporter gene expression and glucose uptake into those insulin target tissues. Although the effects of overexpressing PPARalpha in a specific tissue obviously differ from activating PPARalpha in a systemic manner, studies such as this may influence the development of the next generation of PPAR ligands.